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    Summary
    EudraCT Number:2014-003286-21
    Sponsor's Protocol Code Number:SVUH-UCD-LEAD/CAR/01/2014
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-11-28
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2014-003286-21
    A.3Full title of the trial
    A multicentre, interventional, parallel group, randomised, open-label, exploratory study to assess the earlier introduction of Ivabradine in the Management of Systolic Dysfunction Heart Failure. The QUALIVA study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicentre, interventional, parallel group, randomised, open-label, exploratory study to assess the earlier introduction of Ivabradine in the Management of Systolic Dysfunction Heart Failure. The QUALIVA study
    A.3.2Name or abbreviated title of the trial where available
    QUALIVA
    A.4.1Sponsor's protocol code numberSVUH-UCD-LEAD/CAR/01/2014
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity College Dublin
    B.1.3.4CountryIreland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportServier Laboratories (Ireland) Ltd
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSchool of Medicine & Medical Science
    B.5.2Functional name of contact pointProf Ken McDonald
    B.5.3 Address:
    B.5.3.1Street AddressSt Vincent’s Hospital
    B.5.3.2Town/ cityElm Park
    B.5.3.3Post codeDublin 4
    B.5.3.4CountryIreland
    B.5.4Telephone number3531663 8110
    B.5.6E-mailKenneth.mcdonald@ucd.ie
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Procoralan
    D.2.1.1.2Name of the Marketing Authorisation holderLes Laboratoires Servier
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameIvabradine
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIVABRADINE
    D.3.9.1CAS number 155974-00-8
    D.3.9.4EV Substance CodeSUB08357MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name CARDICOR
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Serono Ltd
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namebisoprolol - Cardicor
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCARDICOR
    D.3.9.3Other descriptive nameBISOPROLOL FUMARATE
    D.3.9.4EV Substance CodeSUB00832MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1.25 to 10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name EUCARDIC
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Products Limited
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCarvedilol
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEUCARDIC
    D.3.9.3Other descriptive nameCARVEDILOL
    D.3.9.4EV Substance CodeSUB06153MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number3.125 to 50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Procoralan
    D.2.1.1.2Name of the Marketing Authorisation holderLes Laboratoires Servier
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameIvabradine
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIVABRADINE
    D.3.9.1CAS number 155974-00-8
    D.3.9.4EV Substance CodeSUB08357MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number7.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Heart Failure with reduced ejection fraction and borderline systolic blood pressure.
    E.1.1.1Medical condition in easily understood language
    Heart Failure with reduced ejection fraction and borderline systolic blood pressure.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level SOC
    E.1.2Classification code 10007541
    E.1.2Term Cardiac disorders
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess whether reducing heart rate with Ivabradine, versus further titration of beta blockade, in patients with HF-REF and borderline systolic blood pressure results in improved 6MWT
    E.2.2Secondary objectives of the trial
    To evaluate the effect of reducing heart rate with Ivabradine, versus further titration of beta blockade in patients with HF-REF and borderline systolic blood pressure on:
    •Quality of Life (KCCQ)
    •Other clinical outcomes (NYHA status, Cardiovascular exams, BNP and eGFR)
    •Becks Depression Score; and
    •To evaluate the safety follow-up in both groups
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Recently prescribed the beta-blocker bisoprolol or carvedilol (a maximum of 4 weeks since initiating treatment and at least one week for bisoprolol and at least two weeks for carvedilol since the last BB dose adjustment with doses not greater than bisoprolol 5mg daily/carvedilol 12.5mg twice daily, to allow further up-titration)
    •Willing to give written informed consent to participate in the study and to comply with the study procedures and restrictions during the study period.
    •Male or female ≥ 18 years
    •Diagnosed with symptomatic HF-REF and LVEF ≤ 40% (measured no longer than 3 months before the selection visit)
    •Systolic CHF class II and III (NYHA class)
    •No evidence of clinical decompensation
    •Electrocardiographic documentation of sinus rhythm with resting heart rate ≥ 70bpm
    •SBP ≤120mmHg and ≥100mmHg
    •Able to walk more than 450 meters within 6 minutes during inclusion visit (INCL)
    •Recently prescribed the beta-blockers bisoprolol or carvedilol and undergoing BB titration (at least one week for bisoprolol and at least two weeks for carvedilol since the last BB dose adjustment), with dose not greater than bisoprolol 5mg daily/carvedilol 12.5mg twice daily, to allow further up-titration)
    •Having completed other drug titration so as to confine the drug manipulation during the study period to a minimum (eg on full dose ACEi/ARB)
    •ICD implantation is acceptable for inclusion. The presence of a CRT device will be assessed on a case by case basis
    E.4Principal exclusion criteria
    •Participation in another study at the same time or within three months prior the selection visit (ASSE) for this study
    •Unable to provide written informed consent
    •Women who are pregnant or breast-feeding or women of child bearing potential not using estro-progestative oral or intra-uterine contraception or implants, or women using estro-progestative oral or intra-uterine contraception or implants but who consider stopping it during the planned duration of the study. Menopause will be defined as absence of menses for ≥ 1 year.
    •Current treatment with beta blocker other than bisoprolol or carvedilol
    •Current treatment with ivabradine or previous treatment in the last 6 months
    •Resting heart rate <70 beats per minute
    •Able to walk more than 450 meters within 6 minutes during inclusion visit (INCL)
    •History of drug or alcohol use that, in the opinion of the investigator, would interfere with adherence to study requirements
    •Known severe renal insufficiency with calculated creatinine clearance ≤15 mL/min/1.732
    •Severe hepatic insufficiency
    •Any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk by participation in the study, or may influence the result of the study
    •Prior or concurrent malignancy within 5 years prior to starting the study treatment
    •Known contraindication/allergy/sensitivity/intolerance to study medications or their ingredients (Ivabradine, Bisoprolol and/or Carvedilol)
    •Documented permanent atrial fibrillation or other cardiac arrhythmia that interferes with the sinus node function, or recent hospitalisation for atrial fibrillation or other cardiac arrhythmia that interfere with the sinus node function within the last 3 months
    •Severe hypotension (<90/50 mmHg)
    •Cardiogenic shock
    •Sick sinus syndrome, sino-atrial block, 2nd and 3rd degree AV-block
    •Unstable or acute heart failure
    •Unstable angina
    •Recent myocardial infarction or coronary revascularisation (less than 2 months),
    •Pacemaker dependent
    •Other clinically significant ECG findings as judged by the investigator
    •Patients with familial history or congenital or substance-induced long QT syndrome or treated with selected QT prolonging products (see section 12.9)
    •Scheduled for procedures requiring general anaesthesia during the study
    •Clinically significant abnormalities as judged by the investigator in haematology and biochemistry parameters. Special attention should be given to potentially significant abnormal values of the renal or liver function test
    •Clinically significant findings as judged by the investigator during the procedures performed at the selection or inclusion visits
    •Any treatment with unauthorised medications (see section 12.9) that could not be interrupted for the duration of the study
    •Patients requiring a treatment that is unauthorised during the study or for whom such a treatment is considered
    E.5 End points
    E.5.1Primary end point(s)
    Difference in meters between the 6MWT performed at baseline (INCL) and at week 18 (W18)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 18
    E.5.2Secondary end point(s)
    Functional status summary score of the Kansas City Cardiomyopathy Questionnaire (KCCQ) assessed at baseline (INCL) and at end of study visit (W18)
    •Other domain scores of the KCCQ assessed at baseline (INCL) and at end of study visit (W18)
    •Functional capacity (NYHA class) and clinical symptoms of heart failure assessed during the study
    •Clinical outcomes assessed during the study
    •BNP measured at baseline (INCL) and at end of study visit (W18)
    •Renal function assessed at baseline (INCL) and at end of study visit (W18)
    •Becks Depression Score assessed at baseline (INCL) and at end of study visit (W18)
    •Number/Time to occurrence of the first event of one of the following: Patient death from any cause, Hospitalisation for any cause, Emergency room visits for any cause, and Out-patients visits for management of clinical deterioration of Heart Failure.
    •Adverse event recording (Safety follow-up)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 18
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    none
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-01-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-08-17
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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